X-68838684-C-T

Variant names:

• chrX-68838684-C-T
• rs104894804
• NM_004429.5:c.196C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004429.5(EFNB1):​c.196C>T​(p.Arg66*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: EFNB1 NM_004429.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.54

Genes affected

EFNB1 (HGNC:3226): (ephrin B1) The protein encoded by this gene is a type I membrane protein and a ligand of Eph-related receptor tyrosine kinases. It may play a role in cell adhesion and function in the development or maintenance of the nervous system. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-68838684-C-T is Pathogenic according to our data. Variant chrX-68838684-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-68838684-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFNB1	NM_004429.5	c.196C>T	p.Arg66*	stop_gained	Exon 2 of 5	ENST00000204961.5	NP_004420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFNB1	ENST00000204961.5	c.196C>T	p.Arg66*	stop_gained	Exon 2 of 5	1	NM_004429.5	ENSP00000204961.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Oct 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg66*) in the EFNB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EFNB1 are known to be pathogenic (PMID: 15959873, 16685650). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with craniofrontonasal syndrome (PMID: 15166289, 15959873, 16685650, 18627045, 23335590, 26586496). ClinVar contains an entry for this variant (Variation ID: 11715). For these reasons, this variant has been classified as Pathogenic. -

Nov 16, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20565770, 26586496, 23335590, 15166289, 18627045, 15959873, 16685650, 31618753) -

Aug 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Craniofrontonasal syndrome Pathogenic:2

Jun 05, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 15, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.80	D
Vest4		0.67
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104894804; hg19: chrX-68058527;